Aminopyridine derivative containing hydroxamic acid fragment as well as application thereof to anti-tumor aspect

An aminopyridine, hydroxamic acid technology, applied in antitumor drugs, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as poor curative effect and easy generation of drug resistance

Active Publication Date: 2018-07-24
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, single-target anti-tumor drugs have problems such as poor efficacy and easy drug resistance, which are not enough to meet the needs of preventing and treating malignant tumors

Method used

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  • Aminopyridine derivative containing hydroxamic acid fragment as well as application thereof to anti-tumor aspect
  • Aminopyridine derivative containing hydroxamic acid fragment as well as application thereof to anti-tumor aspect
  • Aminopyridine derivative containing hydroxamic acid fragment as well as application thereof to anti-tumor aspect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] 7-(4-(4-(6amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin)3-yl)pyrazol-1-yl)piperidine Synthesis of -1-yl-N-hydroxyheptanamide (V-1) and its hydrochloride

[0104] 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (0.5g, 1.3mmol), 1-(4-piperidine-1- (7-Ethyl heptanoate)-4-pyrazole pinacol boron ester (0.68g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) as raw materials, according to class V Compound Synthesis General Method Scheme 1 to synthesize V-1 to obtain 0.35 g of the target compound with a yield of 45%.

[0105] ESI-MS[M+H] + :m / z 593.22

[0106] 1 H NMR (400MHz, DMSO-d 6 )δppm: δ7.78(s,1H),7.63(m,1H),7.52(s,1H),7.42(m,1H),7.20(m,1H),6.89(m,1H),6.14(q ,J=6.7Hz,1H),4.23(s,1H),3.15(m,3H),2.58(s,2H),2.45(s,2H),2.18(m,5H),1.84(m,2H) ,1.60(s,3H),1.34(s,3H),1.26(m,3H)

[0107] Compound V-1 (0.20g, 0.3mmol) was dissolved in isopropanol, concentrated hydrochloric acid was added dropwise, a white solid was pr...

Embodiment 2

[0109] 6-(4-(4-(6amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin)3-yl)pyrazol-1-yl)piperidine Synthesis of -1-yl-N-hydroxycaproamide (V-2)

[0110] 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (0.5g, 1.3mmol), 1-(4-piperidine-1- (6-Ethyl hexanoate)-4-pyrazole pinacol boron ester (0.65g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) as raw materials, according to Class V Compound Synthesis General Method Scheme 1 to synthesize V-2 to obtain 0.39 g of the target compound with a yield of 52%.

[0111] ESI-MS[M+H] + :m / z 579.21

[0112] 1 H NMR (400MHz, DMSO-d 6 )δppm: δ10.49(s,1H),8.81(s,1H),8.00(s,1H),7.75(s,1H),7.58(m,1H),7.53(s,1H),7.45(m ,1H),6.90(s,1H),6.09(q,J=6.7Hz,1H),5.67(s,2H),4.36(m,1H),4.02(m,2H),3.16(m,2H) ,2.97(s,2H),1.99(s,2H),1.80(m,4H),1.60(m,4H),1.23(s,3H).

Embodiment 3

[0114] 5-(4-(4-(6amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin)3-yl)pyrazol-1-yl)piperidine Synthesis of -1-yl-N-hydroxypentanamide (V-3)

[0115] 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (0.5g, 1.3mmol), 1-(4-piperidine-1- (5-Ethyl pentanoate)-4-pyrazole pinacol boron ester (0.64g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) as raw materials, according to Class V Compound Synthesis General Method Scheme 1 to synthesize V-3 to obtain 0.37 g of the target compound with a yield of 51%.

[0116] ESI-MS[M+H] + :m / z 565.20

[0117] 1 H NMR (400MHz, DMSO-d 6 )δppm: δ10.50(s,1H),8.81(s,1H),8.00(s,1H),7.75(s,1H),7.58(m,1H),7.53(s,1H),7.45(m ,1H),6.90(s,1H),6.09(q,J=6.7Hz,1H),5.67(s,2H),4.36(m,1H),4.02(m,4H),3.16(m,1H) ,2.97(s,2H),1.99(s,3H),1.80(m,4H),1.60(m,5H).

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Abstract

The invention provides a hydroxamic acid fragment-containing aminopyridine derivative as shown in a formula V, pharmaceutically acceptable salt thereof as well as application of the aminopyridine derivative to anti-tumor aspect (the formula is shown in the description). The compound has high protein kinase inhibition activity and histone deacetylase inhibition activity, has high inhibition activity on various human tumor cells, has weak inhibition effect on normal cells, has low toxicity and is suitable for being applied to development of anti-tumor medicines.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to aminopyridine derivatives containing hydroxamic acid fragments and their antitumor applications. Background technique [0002] Tumors are the result of multi-gene and multi-pathway interactions. With the deepening of people's understanding of genetics, biochemistry, and oncogene signal transduction, research and development of multi-target, multi-pathway anti-tumor inhibitors to treat tumor resistance Drug resistance and recurrence will be the development direction of anticancer drug research in the future. [0003] In recent years, with the continuous improvement of molecular biology technology and the further understanding of tumor pathogenesis at the cellular and molecular levels, as well as the rapid development of technologies such as combinatorial chemistry, structure-based drug design and computer science, tumor biotherapy has become a reality. Gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/04C07D213/74A61K31/4545A61K31/4439A61K31/44A61P35/00
CPCC07D213/74C07D401/04C07D401/14
Inventor 李建其张保寅张庆伟解鹏孙媛媛
Owner SHANGHAI INST OF PHARMA IND CO LTD
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